Field of Invention
The invention relates to supramolecular structures, also called supramolecular nanoparticles (SNP) prepared using molecular recognition properties of building blocks. The invention also includes methods of producing supramolecular structures using molecular recognition and methods of controlling the size of the nanoparticles produced. The invention also includes methods of using the supramolecular structures to deliver genes, therapeutic compounds, and as photothermal therapy agents.
Discussion of Related Art
Nanoparticle therapeutics are typically particles comprised of therapeutic entities, such as small-molecule drugs, peptides, proteins and nucleic acids, and components that assemble with the therapeutic entities, such as lipids and polymers. Such nanoparticles can have enhanced anticancer effects compared with the therapeutic entities they contain. This is owing to more specific targeting to tumor tissues via improved pharmacokinetics and pharmacodynamics, as well as active intracellular delivery. These properties depend on the size and surface properties (including the presence of targeting ligands) of the nanoparticles
Although an enormous amount of research is ongoing in the area, a majority portion of the work will not be translatable to the clinic. Some of the main obstacles include the use of immunostimulatory components, the use of components that have barriers to large-scale current good manufacturing practice (cGMP) production and/or hurdles in the development of well-defined chemistry, manufacturing and controls assays. A limited number of nanoparticle systems have achieved clinical applications, and information is becoming available to begin to understand some of the issues of moving these experimental systems into humans.
Over the past decades, there have been significant efforts devoted to explore the use of nanoparticles in the fields of biology and medicine. Several different types of nanoparticles have successfully made their ways into pre-clinical studies in animals, clinic trials in patients or even successful commercial products used in routine clinical practice. (Davis et al., Nat. Rev. Drug Discov. 2008, vol. 7, p. 771) For example, gold nanoshells (Loo et al., Technol. Cancer Res. Trea, vol. 3, p. 33, 2004), quantum dots (Gao et al., Nat. Biotechnol., vol, 22, p. 969, 2004; Nie et al., Annu. Rev. Biomed. Eng., vol. 9, p. 257, 2007) and super-paramagnetic nanoparticles, (Jun et al., Angew. Chem., vol. 120, p. 5200, 20080; Jun et al., Angew. Chem. Int. Ed., vol. 47, p. 5122, 2008) which carry target-specific ligands have been employed in in vivo cancer imaging; drug molecules can be packaged into polymer-based nanoparticles and/or liposomes (Heath et al., Annu. Rev. Med., vol. 59, p. 251, 2008; Torchilin et al., Nat. Rev. Drug Discov., vol. 4, p. 145, 2005) to achieve controlled released at disease sites (Napier et al., Poly. Rev., vol. 47, p. 321, 2007; Gratton et al., Acc. Chem. Res., vol. 41, p. 1685, 2008); positively charged nanoparticles can serve as a non-viral delivery system for both in vitro and in vivo genetic manipulation and programming (Davis et al., Nat. Rev. Drug Discov., vol. 7, p. 771, 2008; Green et al., Acc. Chem. Res., vol. 41, p. 749, 2008; Pack et al., Nat. Rev. Drug Discov., vol. 4, p. 581, 2005). However, there remains an imperious desire for developing novel synthetic approaches in order to produce new-generation nanoparticles which have (i) controllable sizes and morphologies, (ii) low toxicity, compatible immunogenicity and in vivo degradability, and (iii) proper surface charges and chemistry for improved physiological stability and longer circulation time.
Noble-metal nanostructures with unique photophysical properties have been considered as prime-candidate agents for photothermal treatment of cancer (Anderson et al., Science, vol. 220, p. 524, 1983; Jain et al., Acc Chem Res, vol. 41, p. 1578, 2008; An et al., Nano Today, vol. 4, p. 359, 2009; Lal et al., Acc Chem Res, vol. 41, p. 1842, 2008). Typically, the photothermal properties of these nanostructures can be controlled by manipulating their sizes and shapes (Lal et al., Acc Chem Res, vol. 41, p. 1842, 2008; Skrabalak et al., Acc Chem Res, vol. 41, p. 1587, 2008). Over the past two decades, significant endeavors have been devoted to produce a variety of gold (Au) nanostructures, e.g., nanoparticles (Lapotko et al., Laser Surg Medi, vol. 38, p. 631, 2006; Huang et al., Lasers Med Sci, vol. 23, p. 217, 2008), nanoshells (Gobin et al., Nano Lett, vol. 7, p. 1929, 2007; Hu et al., J Am Chem Soc, vol. 131, p. 14186, 2009; Kim et al., Angewandte Chemie-International Edition, vol. 45, p. 7754, 2006), nanorods (Dickerson et al., Cancer Letters, vol. 269, p. 57, 2008; Huang et al., Langmuir, vol. 24, p. 11860, 2008) and nanocages (Skrabalak et al., Acc Chem Res, vol. 41, p. 1587, 2008; Chen et al., Nano Lett, vol. 7, p. 1318, 2007; Au et al., ACS Nano, vol. 2, p. 1645, 2008), which are able to overcome limitations of the organic dye-based photothermal agents (Huang et al., Lasers Med Sci, vol. 23, p. 217, 2008), such as low light absorption and undesired photobleaching. In order to harvest/generate sufficient energy to damage tumor cells, the sizes of these nanostructure-based agents are required in the range of tens to hundreds nm (Lowery et al., Clin Cancer Res, vol. 11, p. 9097s, 2005). However, the relatively “large” sizes of the agents often lead to poor bio-clearance (i.e., accumulation in liver, spleen and kidney), representing a major obstacle toward their in vivo applications (Mitragotri et al., Nat Mater, vol. 8, p. 15, 2009; Choi et al., Nat Biotechnol, vol. 25, p. 1165, 2007; Nel et al., Nat Mater, vol. 8, p. 543, 2009). Alternatively, the photophysical properties of noble-metal nanostructures can be systematically altered by forming aggregates via self assembly (Khlebtsov et al., Nanotechnology, vol. 17, p. 5167, 2006; Lu et al., J Mater Chem, vol. 19, p. 4597, 2009; Zhuang et al., Angew Chem Int Ed Engl, vol. 47, p. 2208, 2008; Troutman et al., Adv Mater, vol. 20, p. 2604, 2008; Ofir et al., Chem Soc Rev, vol. 37, p. 1814, 2008; Elghanian et al., Science, vol. 277, p. 1078, 1997; Lin et al., Adv Mater, vol. 17, p. 2553, 2005; Katz et al., Angew Chem Int Ed Engl, vol. 43, p. 6042, 2004; Cheng et al., Nature Nanotechnology, vol. 3, p. 682, 2008; Maye et al., J Am Chem Soc, vol. 127, p. 1519, 2005; Niemeyer, Angewandte Chemie-International Edition, vol. 40, p. 4128, 2001; Klajn et al., Nat Chem, vol. 1, p. 733, 2009). It has been observed (Lapotko et al., Cancer Lett, vol. 239, p. 36, 2006) that antibody-assisted aggregation of Au-nanoparticles on cell membranes or in intracellular environments led to the enhancement of photothermal performance, as a result of the collective effects (Govorov et al., Nano Today, vol. 2, p. 30, 2007; Richardson et al., Nano Lett, vol. 9, p. 1139, 2009) associated with the assembled structures. Therefore, self-assembly of small noble-metal building blocks, i.e., noble-metal colloids with the sizes (<8 nm) (Mitragotri et al., Nat. Mater., vol. 8, p. 15, 2009; Choi et al., Nat Biotechnol, vol. 25, p. 1165, 2007; Nel et al., Nat Mater, vol. 8, p. 543, 2009) compatible with renal clearance, would provide a promising approach toward a new type of noble-metal photothermal agents.
Gene therapy generally requires delivery vehicles that are capable of (i) carrying/protecting genetic materials, e.g., DNA and siRNA, and (ii) target-specific delivery to desired tissues or subsets of cells (Kim et al. Nat Rev Genet, vol. 8, p.p. 173-184, 2007). Over the past decades, significant endeavors have been devoted to develop non-viral gene delivery vehicles (Glover et al., Nat Rev Genet, vol. 6, pp. 299-310, 2005; Rosi et al., Chem. Rev., vol. 105, pp. 1547-1562, 2005) as alternatives to their viral counterparts, whose applications are restricted due to the potential safety issues and complex processes of preparation. Among the existing non-viral gene delivery systems (Niidome et al., Gene Ther., vol. 9, p. 1647-1652, 2002; Prata et al., Chem. Commun., pp. 1566-1568, 2008; Woodrow et al., Nat. Mater., vol. 8, pp. 526-533, 2009; Chen et al., Chem. Commun., pp. 4106-4108, 2009; Torchilin et al., Proc Natl Acad Sci USA, vol. 100, pp. 1972-1977, 2003), nanoparticle-based gene delivery vehicles (Liang et al., Proc Natl Acad Sci USA, vol. 102, pp. 11173-11178, 2005; Kumar et al., Chem. Commun., pp. 5433-5435, 2009; Bazin et al., Chem. Commun., pp. 5004-5006, 2008; Cheon et al., Acc. Chem. Res., vol. 41, pp. 1630-1640, 2008) have received extensive attention. Nanoparticles have been regarded as promising transfection agents for effective and safe delivery of nucleic acids into specific type of cells or tissues, providing an alternative gene manipulation/therapy strategy to viral delivery. However, the slow, multistep synthetic approaches restrict the diversity of existing delivery materials, representing a major obstacle to achieving optimal transfection performance.